Process for the manufacture of 18-substituted steroids



United States Patent Office Patented June 4, 1963 3,092,627 PROCESS FORTHE MANUFACTURE OF ISSUBSTITUTED STEROIDS Albert Wettstein, Riehen, andGeorg Anner, Jaroslav Kalvoda, and Charles Meystre, Basel, Switzerland,assignors to Ciba Corporation, a corporation of Delaware No Drawing.Filed July 10, 1961, Ser. No. 122,659 Claims priority, applicationSwitzerland July 19, 1960 18 Claims. (Cl. 260-23955) The presentinvention provides a new process for the manufacture of 18-substitutedsteroids, more especially for the manufacture of l8-cyano compounds ofthe pregnane series.

Said compounds are valuable intermediates for the manufacture ofIll-oxygenated pregnanes which in their turn can be used for themanufacture of compounds of the type of the adrenocortical hormonealdosterone and related substances which have an outstandingthereapeutic importance in the regulation of a disturbed mineralmetabolism.

The new process consists in treating an 18-unsubstitutedZO-hydroxy-ZO-cyano compound of the pregnane series with a compoundcontaining a positive, monovalent halo gen having an atomic weight above19 under conditions bringing about homolytic cleavage of resulting'ZO-hypohalites, and if desired, the IS-cyano group in a resulting18-cyano-20-oxo-pregnane compound is reduced to an 18- aminomethylgroup, if desired after ketalization of any free oxo group that may bepresent.

The compound containing a monovalent, positive halogen, especiallychlorine, bromine or iodine, may be e.g. an N-halogencarboxylic acidamide or imide, for example, N-chl-oracetamide, N-bromacetamide,N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide,1,3-dibromo-5,5-dimethyl-hydantoin, or'it may be chlorocyan, bromocyanor iodocyan. There may also be used hypohalous acids or derivativesthereof, eg alkylhypohalites, such as tertiary butylhypochlorite,tertiary butylhypobromite. Alkylhypoiodites can be prepared, forexample, from heavy metal oxides, such as mercury oxide, silver oxide,lead oxide, and the like, with iodine and alcohols. There are alsosuitable acylhypohalites which can be obtained especially advantageouslyfrom heavy metal acylates, e.g. acetates, propionates, trifluoracetates,benzoates, etc. of metals of the first and second subgroups of thePeriodic Table, e.g. from acylates of silver or mercury with chlorine,bromine or iodine. An advantageous method of preparing theacylhypoiodites consists in reacting iodine with lead tetraacylates, inwhich process lead diacylates and acylhypoiodites are formed.Monovalent, positive iodine is also contained in the compoundsof iodinewith other halogens, that is to say, in iodine chloride or iodinebromide. It is often of advantage to prepare the necessary halogenreagent, especially the hypohalite, in the reaction solution.

One way of performing the process consists in dissolving or suspendingthe starting material in a solvent which is inert toward the oxidant,e.g. a hydrocarbon, then add ing lead tetraacetate, iodine and a weakbase, for example, calcium carbonate, and heating and stirring thereaction solution at atmospheric or superatmospheric pres sure. In ananalogous manner the reaction can also be performed with iodine andsilver acylates or iodine and mercury acylates, for example, theacetates thereof, or complexes formed from these reagents. Especiallysuitable solvents are saturated, cyclic hydrocarbons, such ascyclohexane, methylcyclohexane, dimethyl-cyclohexane, but aromatichydrocarbons, such as benzene or halogenated hydrocarbons, such ascarbon tetrachloride, hexachloro butadiene or mixtures of these solventscan also be used.

The reaction is conveniently performed at a raised temperature, forexample, between 50 and C. Moreover, it can be accelerated byirradiation of the reaction solution with visible and/ or ultravioletlight. Adding free halogen, especially iodine, to the reaction solutionis of advantage in many instances.

The products obtained by the present process are 18-cyano-ZO-oxo-pregnanes formed by the migration of the cyano group withsimultaneous oxidation of the 20-hydroxyl group. This reaction of thepresent invention is all the more surprising as it is already known thata 20- hydroxy-pregnane containing no cyano group at carbon atom 20yields under the specified conditions 18:20-oxido compounds andderivatives thereof.

The ZO-hydroxy-ZO-cyano-pregnanes used as starting materials contain inthe ring system more especially in one or several of the positions 1, 2,3, 4, 5, 6, 7, 8, '9, 10, ll, 12, 14, 15, 16, 17, 21 furthersubstituents, such as esterified or etherified hydroxyl groups, free orfunctionally converted oxo groups, alkyl groups such, for example, asmethyl groups, or halogen atoms. The term functionally converted oxogroups" refers to ketalized or enolized oxo groups. Furthermore, thestarting materials may contain double bonds or oxido groups, for examplestarting from carbon atom 5 and/or in the 9: I l-position. Specificstarting materials are, for example, the ZO-cyano-hydrins of3-acyloxy-2'0-oxo-pregnanes which may be saturated or unsaturated in the5:6-position, for example 3B-acetoxy- 2=0 oxo 5 m-pregnane, 3p:11u-diacetoxy-ZG-oXO-Sa-pregnane, 3a:11adiacetoxy-ZO-OxQ-SB-pregnane,3e-acetoxy- 1 1 :ZO-dioxo-Sfi-pregnane, A -3p-acetoxy-20oxo-pregnene, orZO-cyano-hydrins of n -3z2o-dioxo-pregnenes such as progesterone,ll-keto-progesterone, lle-acetoxy-progesterone and the corresponding A-3-ethylene-ketals.

, If desired, the reaction of the invention can be followed by afunctional conversion of any 0x0 or hydroxyl groups present, that is tosay they may be ketalized, or esterlfied or etherified, or protected oxoor hydroxyl groups may be liberated. r

The invention further provides 18-cyano-steroids, more especiallyIS-cyano-pregnanes, preferably such as contain in positions 3 and 20,and if desired also in positions 11 and/or 21, an oxygen function. Asspecific compounds there may be mentioned IS-cyano-progesterone,18cyanol la-hydroxy-progesterone, IB-cyano-l lp-hydroxy-progesterone;IB-cyano-l l-oxo-progesterone, and the corresponding 3-monoketals and3:20-diketals; 3-hydroxy-l8- cyano 20 oxo-pregnanes, 3:ll-dihydroxy-18-cyano-20- Oxo pregnanes, 3hydroxy-l1:20-dioxo-l8-cyano-pregnanes, the corresponding Sa-pregnanes,and ketals and esters thereof.

The present invention also includes IS-aminomethylsteroids, moreespecially unsubstituted and substituted 18-. aminomethyl-Saand-5B-pregnanes, preferably such as contain in positions 3 and 20, ifdesired also in position 11, an oxygen function. These compounds areobtained by reducing the 18-cyano compounds with a complex metalhydride, for example with lithium aluminum hydride or by catalyticreduction, preferably in an acid solution. The resulting aminomethylcompounds can be substituted, that is to say acylated or alkylated, atthe nitrogen atom in the known manner. As specific examples there may bementioned l 8-aminomethyl-progestepgne, 18-aminomethyl 11a.hydroxy-progesterone, 18-aminomethyl- 11B hydroxy-progesterone,18-aminomethyl-l 1-oxo-progesterone and the corresponding 3:20-diketalsand derivatives acylated or alkylated at the nitrogen atom; also 3-hydroxy l8 aminomethyl-ZO-oxo-pregnanes, 3: 1 l-dihydroxy l8 aminomethyl20-oxo-pregnanes 3-hydroxy- 1 1 :ZO-dioxo-l 8-amlnomethyl-pregnanes,theaorresponding Sa-pregnanes, as well as ketals, esters, N-a'cylatedand N-alkylated derivatives thereof.

In the aforementioned esters, the acid radicals are especially those ofaliphatic, cycloaliphatic, araliphatic or aromatic carboxylic acidshaving 1 to 15 carbon atoms, for example, formates, acetates,propionates, butyrates, trimethyl acetates, enanthates, capro-nates,decanoates, cyclopentyl propionates, valerates, benzoates, furoates,hexahydrobenzoates, phenylpropionates, trifluoracetates, ethylcarbonates or methyl carbonates, etc.

The aforementioned compounds can be degraded to Iii-oxygenated pregnanesin the following manner: The free oxo groups present in the 18-cyanidesare protected by ketalization, for example by heating the compounds withethylene glycol in the presence of a small amount of paratoluenesulfonicacid and in the ketals so formed the nitrile group is reduced, forexample with lithium aluminum hydride, to form the amino group. In the18- aminomethyl compounds this group is quaternated, for example withmethyliodide in the presence of a base such as potassium carbonate, andfinally the quaternary base. is subjected to the degradation accordingto Hoffmann by being heated with an alkali or silver oxide. In thismanner there are obtained 18-methylene-pregnanes in which the doublebond is split either by ozonization or by oxidation with chromic acid inglacial acetic acid or by hydroxylation with osmium tetroxide andsubsequent oxidative glycol splitting with per-iodic acid or leadtetraacetate. Depending on the type of oxidizing agent used there areobtained 18-oxo-pregnanes or pregnane-IB- acids. The further conversionof these compounds into aldosterone and related substances follows theknown pattern.

The following examples illustrate the invention.

Example I A suspension of 1.0 gram of calcium carbonate and 3.0 grams oflead tetraacetate in 100 cc. of cyclohexane is heated to 80 C. and thentreated with 0.80 gram of iodine, and the mixture is boiled withstirring for 1 hour in the dark. 500 mg. of 3fl-aeetoxy-20cyano-20-hydrQxy-Sa-pregnane are then added and the reaction mixture is refluxedfor 2 to 3 hours in daylight. When the solution displays only a slightlypinkish color, it is cooled, filtered, the inorganic residue isexhaustively washed with ether, and the filtrate is successivelyagitated with sodium thiosulfate solution of 10% strength and water,and, without being dried, evaporated under vacuum at 30-40 C. Theslightly colored, crystalline residue is washed with petroleum ether andthen recrystallized from ether-l-petroleum ether. To decolorize theproduct completely it may be filtered through a column of silica gel.Yield: 284 mg. of 3fi-acetoxy-1S-cyano-ZO-oxo-Sepreg-uane melting at169-170 C. The infra-red spectrum of the compound contains inter aliaabsorption bands at 4.45, 5.78, 5.85, 8.06, 8.40, 8.50, 8.67, 9.75 and1050 In the NMR-spectrum the maximum associated with the C-18 methylgroup at 355 cycles is absent, but maxima occur at 274, 258 and 339cycles caused by the presence of protons of the acetate group and of theacetylmethyl -211 and of the 0-19 methyl group respectively. A shoulderat 260 cycles could be attributed to the --CH -CN grouping at carbonatom 18.

Example 2 A suspension of 4.00 grams of calcium carbonate and 18.00grams of pre-dried lead tetraacetate in 800 cc. of cyclohexane is heatedto 80 C., treated with 4.80 grams of iodine and boiled for 45 minutes inthe drak. 2.00 grams of 3,3:11u diacetoxy 20-cyano-20-hydroxy-5mpregnaneare added and the mixture is refluxed with stirring in daylight or 3%hours. The reaction solution is cooled, filtered, the inorganic residueis thoroughly washed with ether, and the filtrate is washed with coldsodium thio-sulfate solution of strength and then with water and,without being dried, evaporated under vacuum at a bath temperature of35-40 C. Subsequent crystallization of the solid, brownish residue frommethylene chloride-l-petroleum ether yields 1.060 gram of 35:11:;diacetoxyd8-cyano-20-oxo-5a-pregnane melting at 211 C. which inter aliadisplays the following bands in the infra-red spectrum: 4.45, 5.78,5.86, 7.35, 8.10, 8.40, 8.70, 8.86, 9.75 and 10.35

Example 3 2.50 grams of AM -ethylenedioxy-ZO-cyano-20-hydroxy pregneneare reacted with 22.5 grams of lead tetrracetate, 6.00 grams of iodineand 5.00 grams of calcium carbonate in 1 liter of cyclohexane asdescribed in Examples 1 and 2. Working up followed by crystallization ofthe crude product from methylene chloride+petroleum ether gives a 35-40%yield of A -3-ethylenedioxy-18-cyano-20- oxo-pregnene melting at l93-l96C. The infra-red spectrum of the compound contains inter alia thefollowing bands: 4.40, 5.86, 6.90, 7.37, 7.62, 8.25, 9.05, 9.15, 9.75,10.10, 10.45, 10.55, 11.50 and 12.20 4.

Example 4 A mixture of 20.0 grams of calcium carbonate, 92 grams of leadtetraacetate, 24.0 grams of iodine and 3.5 liters of cyclohexane isboiled for 1 hour in the dark, then treated with 10.0 grams of A-3-oxo-20-cyano-20-hydroxy-pregnene (progesteronoZO-cyanohydrin), andthe whole is refluxed with stirring for 3 hours in daylight. working upas described in Examples 1 and 2 yields 12.65 grams of an oily, coloredproduct which is dissolved in 2.6 liters of benzene, treated with 400cc. of ethylene glycol and 1.0 gram of para-toluenesulfonic acid andketalized for 16 hours. Usual working up yields 11-12 grams of a crudecrystallizate. After recrystallization from methylenechloride-l-pctroleum ether there are obtained 2.80 to 3.00 grams of d-3z20-bis-ethylenedioxy- IS-cyanmpregnene (l8-cyano-progesteronediketal) melting at 185-486" C. in the form of fine needles. Theinfrared spectrum of the compound reveals inter alia the followingabsorption bands: 4.42, 9.00, 9.10, 9.20 and 9.57

Example 5 300 mg. of the A -3-ethylenedioxy-18-cyano-20-oxopregnenedescribed in Example 3 are dissolved in cc. of benzene and mixed with 15cc. of ethylene glycol and 50 mg. of para-toluenesulfonic acid, and themixture is boiled with stirring for 16 hours with the use of a waterseparator. The cooled reaction mixture is poured into ice-water, dilutedwith ether, washed with saturated so dium b-i-carbonate solution andthen with water, dried and evaporated under vacuum. Recrystallization ofthe residue from methylene chloride+petroleum ether yields 295 mg. of 15-3:20-bis-ethylenedioxy-1S-cyano-pregnene melting at 185-186 C., whichis identical with the product described in Example 4.

Example 6 A suspension of 500 mg. of A--3-ethylenedioxy-18-cyano-20-oxo-pregnene in 25 cc. of acetone istreated with 60 mg. of para-toluenesulfonic acid, with the startingmaterial gradually passing into solution, and the solution is then keptfor 15 hours at 20 C. The solvent is then extensively evaporated undervacuum, the residue (about 3 cc.) is taken up in ether, washed withsaturated sodium bicarbonate solution and then with water, dried andevaporated, to yield 425 mg. of a colorless, oily substance.Chromatography on alumina and recrystallization from acetone-l-pentaneyields pure l8-cyano-progesterone, melting at 134-136 C. Its infra-redspectrum contains inter alia absorption bands at 4.40, 5.86, 6.00, 6.20,6.90, 7.40, 8.15, 8.65, 10.55 and 11.50/L.

Example 7 A solution of 700 mg. of BB-acetoxy-18-cyano-20-oxo-5a-pregnane and 45 mg. of para-toluenesulfonic acid in cc. of benzeneand 15 cc. of ethylene glycol is boiled with stirring for 16 hours withthe use of a water separator. Usual working up yields 751 mg. of crudeketal.

After two recrystallizations from methylene chloride+ methanol there areobtained 558 mg. of 3fl-acetoxy-l8- cyano-ZO-ethylenedioxy-Sa-pregnanemelting at 170l71 C. Another 50 mg. of the same product can be obtainedfrom the mother liquor. The infra-red spectrum of the compound revealsinter alia bands at 4.45, 5.80, 6.95, 7.30, 8.07, 8.70, 8.90, 9.00,9.35, 9.60, 9.75, 10.40, 10.70, 11.01 and 11.35,.

When the acetate described above is hydrolysed with potassium carbonatein methanol at 20 C., 3,8-hydroxyl8-cyano-20-ethyIenedioXy-Suregnanemelting at 221- 222 C. is obtained; its infra-red spectrum containsinter alia the following absorption bands: 2.75, 4.43, 6.90, 7.30, 8.25,8.90, 9.00, 9.35, 9.65, 10.60 and 11.05;.

Example 8 A solution of 500 mg. of 3fi-acetoxy-18-cyano-20-ethyIenedioXy-Saregnane in 20 cc. of absolute tetrahydrofuran is stirreddropwise with external cooling into a suspension of 500 mg. of lithiumaluminum hydride in 20 cc. of tetrahydrofuran, and the reaction mixtureis then refluxed for 2 hours. The excess reagent is decomposed withaqueous sulfate solution while supplying strong external cooling, andthe small excess of water is taken up with anhydrous sodium sulfate. Thewhole is filtered, the residue is thoroughly washed with tetrahydrofuranand methylene chloride, and the filtrate is evaporated under reducedpressure, to yield 425 mg. of3fl-hydroxy-l8-aminomethyl-ZO-ethylenedioxy 50: pregnane melting at185l90 C. The infra-red spectrum of the compound contains characteristicabsorption bands at 2.75, 6.30, 6.90, 7.30, 8.75, 9.35, 9.60, 9.70,10.50, 11.30 and 11.95 4.

Example 9 A solution of 400 mg. of 3fi-hydroxy l8-aminomethyh2O-ethyIenediOXy-Sa-pregnane in 10 cc. of ethanol is treated with 2.5cc. of methyl iodide and 2.5 grams of potassium carbonate and thenstirred under reflux. After 3, and after 12 hours, 2.5 cc. of methyliodide and 2.5 grams of potassium carbonate are added and the whole isboiled for another 3 hours. The reaction mixture is filtered oil toremove inorganic salts, and the latter are exhaustively Washed withmethanol and ethanol, and the filtrate is evaporated. The residue isrepeatedly extracted by being boiled with chloroform, and the extract isevaporated under vacuum, to yield 305 mg. of amorphous methiodide ofBfi-methoxy-lS-dimethylamino-methyl-ZO- cthyIenedioXy-Sa-pregnane which,without having been purified, is dissolved in 20 cc. of methanol andagitated for 2 hours with a suspension of freshly precipitated silverhydroxide which has been washed until neutral. The inorganic precipitateis filtered ofl", the solution is evaporated under vacuum, and theresidue is pyrolysed at 180420 C. The reaction mixture is taken up inether and Water, the ethereal layer is washed with dilute hydrochloricacid and then with water, dried and evaporated under vacuum, to yield3p-methoxy-l8-methylene- 20-oxo-5u-pregnane.

Example 10 When the suspension has cooled somewhat, 18 g. of iodine and10 g. of A -3p-acetoxy-20-hydroxy- ZO-cyano-pregnene are added. Heatingis continued for 2 hours while irradiating with a 500 w. lamp. 2 litersof cyclohexane are then distilled off, the suspension cooled to 20 C.and treated with a solution of 50 g. sodium acetate in l cc. of theethanol+chloroform mixture and, after the addition of water, the aqueouslayer is separated. The chloroform solution is washed once more withwater and the aqueous solution extracted twice with chloroform. Theextracts are dried with sodium sulfate and treated with 10 g. ofanhydrous sodium acetate and 20 cc. of glacial acetic acid, and thewhole evaporated under reduced pressure. The residue is dissolved in cc.of glacial acetic acid, the solution heated on the water bath for 30minutes, then cooled to 15 C. and agitated for 20 minutes, whilegradually adding a totalof 20 g. of zinc powder. The suspension is thenfiltered with suction, the residue washed with acetone, and the filtrateevaporated in vacuo. The filter residue is dissolved in ether, theethereal solution washed with Water, sodium bicarbonate solution, andwater, and then dried and evaporated under reduced pressure. Theresiduglll g.) is dssolved in methylene chloride, and chromatographedover g. of silica gel (containing 7.5% of water). The first fractionseluted with methylene chloride contains some A-3B-acetoxy-2O-oxo-pregnene; they are followed by mixtures and, finally,A -3fi-acetoxy-18-cyano- 20-oxo-pregnene. Yield 4.02 g. This substanceis recrystallized from a mixture of acetone and isopropyl ether afterwhich it has a double melting in that it first melts at 137 C.,solidifies again, and definitely melts at 147 C. In the IR spectrum, inshows a nitrile band at 4.5;.

Example 11 5 g. of silver acetate, 4.5 g. of iodine, and 2.5 g. of3fl-acetoxy-ZO-ihydroxy-ZO-cyano-Sa-pregnane are covered with 200 cc.oi'gyclohexane. The mixttu'eis stirred and refluxed while'bje'ingirradiated with a 250 w. lamp. After turned yellowis cooled,

i e residue is dissolved 1n methylene chloride and chromatographed over34 g.

The first fractrons eluted with methylene chloride contain Bp-acetoxyf0an frac- 17;: mixture of meth II" ride and isopropyIlh er. There isobtained in this manner the 3B-acetoxy-IS-cyano-20-oxo-5a-pregnane inthe form of fiat needles of melting 'point 169-170 C. The compound isidentical with that described in Example 1.

Example 12 being stirred, and boiled under reflux. another 1.9 grams ofiodine are added and stirring is continued for 45 minutes withirradiation. The cooled suspension is then suction-filtered. Theinsoluble residue is washed with carbon tetrachloride, the solutionagitated with 2 N-sodium thiosulfate and water, did and evaporated underreduced pressure. The residfi' is dissolved in 20 cc. of glacial aceticacid and agitated for 20 minutes at 20 C. with a total of 20 grams ofzinc powder added in portions. The suspension is then filtered withsuction, the residue Washed with acetone and the solution evaporatedunder tion-residue is taken up in ether.

graphed on 50 grams of silica gel (containing 7.5% of water). The firstmethylene chloride fractions contain derivatives containing iodine. Onrecrystallizing the subsequent residues of the methylene chloridefractions from isopropyl ether there are obtained 1.25 grime ofmethylene chloride, it

A -3B-acetoxy-lS cyauo-ZO-oxo-pregnene having a double melting point at137 and 147 C. The further methylene chloride and methylenechloride-l-acetone fractions contain amorphous products.

What is claimed is:

1. Process for the manufacture of 18-cyano-20-oxopregnane compounds,wherein 18-unsubstituted 20-hydroxy-ZO-cyano compounds of the pregnaneseries are heated to a temperature above 50 C. and below 150 C. with acompound yielding positive, monovalent iodine.

2. Process according to claim 1, wherein the lS-cyano group in aresulting 18-cyano-20-oxo-prcgnane compound is reduced to an18-aminomethyl group, after ketalization of any free oxo group that maybe present.

3. Process according to claim 1, wherein ZO-hydroxy- ZO-cyano-pregnanecompounds are treated with compounds containing monovalent, positiveiodine.

4. Process according to claim 1, wherein alkyl hypohalites are used.

5. Process according to claim 1, wherein acylhypohalites are used.

6. Process according to claim 1, wherein lead tetraacetate and iodineare used.

7. Process according to claim 1, wherein the reaction is performed in arnonocyclic alicyclic hydrocarbon.

8. Process according to claim 1, wherein the reaction is performed in alower aliphatic halogenated hydrocarbon.

9. Process according to claim 1, wherein the reaction solution isirradiated with ultraviolet light.

10. l8-cyano-progesterone.

1 1. A -3-ethylenedioxy-18-cyano-20-oxo-pregnene.

12. A -3:ZO-bisethylenedioxy-IS-cyanO-pregnene.

13. 33-acetoxy-18-cyano-20-oxo-5wpregnane.

14. A -3fl-acetoxy-lS-cyano-ZO-oXo-pregnene.

15. 35: 11a-diacetoxyd8-cyano-20-oxo-5u-pregnane.

l6. 3fl-hydroxy-18-aminomethyl 20-ethylenedioxy-5upregnane.

17. A member selected from the group consisting of a compound of theformula:

wherein R represents a member selected from the group consisting of. anoxo group, a ketalized oxo group, a hydrogen atom together with ahydroxy group, a hydrogen atom together with an esterified hydroxylgroup, a hydrogen atom together with an etherified hydroxyl group, Rstands for a member selected from the group consisting of two hydrogenatoms, a hydrogen atom together with an esterified hydroxyl group and anoxo group, R a member selected from the group consisting of a hydrogenatom, a hydroxyl group, an esterified hydroxyl group and R for a memberselected from the group consisting of a free and a ketalized 0x0 group,and their derivatives having a double bond starting from the 5 carbonatom.

18. A member selected from the group consisting of a compound of theformula:

wherein R represents a member selected from the group consisting cl": anoxo group, a ketalized oxo group, a hydrogen atom together with ahydroxy group, a hydrogen atom together with an esterified hydroxylgroup, a hydrogen atom together with an etherified hydroxyl group, Rstands for a member selected from the group consisting of two hydrogenatoms, a hydrogen atom together with an esterified hydroxyl group and anoxo group, R a member selectmd from the group consisting of a hydrogenatom, a hydroxyl group, an esterified hydroxyl group and R for a memberselected from the group consisting of a free and a ketalized oxo group,their N- alkylated derivatives, their N-acylated derivatives andderivatives of said compounds having a double bond starting from the 5carbon atom.

No references cited.

1. PROCESS FOR THE MANUFACTURE OF 18-CYANO-20-OXOPREGNANE COMPOUNDS,WHEREIN 18-UNSUBSTITUTED 20-HYDROXY-20-CYANO COMPOUNDS OF THE PREGNANESERIES ARE HEATED TO A TEMPERATURE ABOVE 50*C. AND BELOW 150*C. WITH ACOMPOUND YIELDING POSITIVE, MONOVALENT IODINE.